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Zinc-Induced Conformational Transitions in Human Islet Amyloid Polypeptide and Their Role in the Inhibition of Amyloidosis
journal contribution
posted on 2018-10-09, 00:00 authored by Alexandre
I. Ilitchev, Maxwell J. Giammona, Jurgen N. Schwarze, Steven K. Buratto, Michael T. BowersType-2
diabetes mellitus (T2DM) is a disease hallmarked by improper
homeostasis within the islets of Langerhans of the pancreas. The most
critical species affected is insulin, which is produced by the β-cells
of the islets, but there are a number of other species copackaged
and cosecreted within the insulin granules. This includes zinc, which
exists in high (millimolar) concentrations within the β-cells,
and islet amyloid polypeptide (IAPP), which is an amyloid peptide
thought to induce β-cell apoptosis through self-association
into toxic amyloid oligomers. Zinc is essential in the packaging of
crystalline insulin within the vesicles but it can also bind and interact
with IAPP. This implies a complex relationship between all three species
and diabetes, particularly in the structure and function of toxic
IAPP aggregates. Atypical (low or high) concentrations of zinc generally
appear to correlate with increased hIAPP aggregation, whereas physiological
zinc concentrations have an inhibitory effect. To better understand
how zinc ions alter the monomer and oligomer structure of hIAPP in
vitro, we employ a combination of ion mobility mass spectrometry and
atomic force microscopy. We observe an increase in the extended β-hairpin
conformation of hIAPP when it is bound to zinc. With sufficiently
low concentrations of zinc this could result in an association site
for zinc-free hIAPP, promoting amyloid aggregation. At high zinc concentrations,
we see the appearance of a secondary zinc association site whose coordination
could account for the loss of inhibition at high zinc concentrations.
Generally, it appears that zinc preferentially stabilizes the β-hairpin
conformation of hIAPP and the population of zinc-bound hIAPP in solution
determines what effect this has on amyloid aggregation.